OP0110 SINGLE CELL RNA-SEQ DISSECTION OF THE SYNOVIAL FLUID IN PSORIATIC ARTHRITIS PATIENTS IDENTIFIES MYELOID CELL SUBSETS RELATED TO TREATMENT RESPONSE WITH BDMARDS
Authors: R. Tzemach, O. Elkayam, A. Polachek, V. Furer, S. Y. Wang, E. David, I. Amit
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Psoriatic arthritis (PsA) is a complex chronic inflammatory disease involving aberrant activation of the innate and the adaptive immune systems<sup>[1]</sup>. While the adaptive system in the synovial fluid of PsA patients has been recently described at a single cell level <sup>[2]</sup>, a comprehensive map of the myeloid compartment is still lacking. Anti TNF agents are commonly used as the first biologic DMARDs (bDMARDs) after failure of conventional DMARDs (cDMARDs), though up to 30-40% of PsA patients are anti TNF non-responders<sup>[3]</sup>. The inflammatory pathways leading to anti TNF or other bDMARDs resistance are unknown and biomarkers to predict treatment response are scarce. <h3>Objectives</h3> 1. To construct a comprehensive immune map of the myeloid compartment in the synovial fluid of naïve and treated PsA patients. 2. To identify gene signatures and immune pathways characteristic of anti TNF or other bDMARDs non-responders. <h3>Methods</h3> This pilot study included PsA patients with active knee arthritis enrolled according to CASPAR criteria, including naïve and treated patients. We obtained synovial fluid by intra-articular aspiration of the involved knee. For each patient we performed single-cell sorting for CD45+ and MHCII+/CD11c+ to enrich for the myeloid compartment (particularly, dendritic cells and monocytes). We used single cell RNA-seq to dissect the immune landscape of the synovial fluid in PsA patients. Osteoarthritis patients with knee involvement were enrolled as a control. PsA Patients were followed for a minimum of 7 months from sampling day (range 7-30 months) and categorized as responders or non-responders according to the DAPSA score. <h3>Results</h3> We analyzed a total of 91,837 cells from 33 PsA Patients (11 naive, 22 under cDMARDs and bDMARDs: 9 anti-TNF and other 9 bDMARDs) and 7 controls (OA). The synovial fluid myeloid compartment of PsA patients was composed of intermediate monocytes (CD14+ CD16+); TREM2 macrophages; conventional dendritic cells: cDC1 (XCR1, CLEC9A), cDC2 (CD1c, CLEC10A) and migratory DCs (mDC: CCR7, LAMP3, IDO1). Intermediate monocytes were the most abundant cell type in the myeloid compartment. Compared to OA controls, PsA patients' synovial fluid was enriched with T regulatory cells (Treg: CD4+ FOXP3+) and migratory DCs (mDC: CCR7, LAMP3, IDO1). Tregs and TREM2 macrophages were more prevalent among treated than naïve PsA patients. We identified a unique cluster of cDC2 and monocytes with shared molecular signature, characteristic of anti TNF or other bDMARDs non-responders. These clusters demonstrated a high expression of interferon signature genes (ISG15, ISG20, IFI27, IFI6, IFIT3, STAT1) and genes related to the immunoproteasome (PSMB9, PSMB8, PSME2, PSME1, POMP). Two patients with severe deformative PsA highly refractory to treatment demonstrated a distinct cDC1 cluster with a high expression of inhibitory genes, such as IDO1, IL4I1, CMTM6 and NFKB1A. <h3>Conclusion</h3> Our study provides the first unbiased map of the myeloid compartment of the synovial fluid of PsA patients. We identified clinically significant cell-subsets within the cDC2 and monocytes populations associated with anti -TNF or other bDMARDs non-response, illuminating potential biomarkers and future therapeutic targets. <h3>References</h3> [1]Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. <i>Lancet</i>. 2018. [2]Penkava F, Velasco-Herrera MDC, Young MD, et al. Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis. <i>Nat Commun</i>. 2020. [3]Noviani M, Feletar M, Nash P, Leung YY. Choosing the right treatment for patients with psoriatic arthritis. <i>Ther Adv Musculoskelet Dis</i>. 2020. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.